Prosthetic patches are widely used for repairs of vasculature, congenital diaphragmatic hernia, orthopedic and fascial defects, as well as in reconstructive surgery and other types of tissue repair. Historically, the first choice of patch material for blood vessels was autogenous saphenous veins, but a separate harvest procedure on patients, risk of infection, and early reports of vein patch blowout led to surgeons using “off-the-shelf” prosthetic materials. Currently, in addition to autogenous saphenous veins, bovine or porcine pericardiums, their decellularized derivatives, and synthetic polymeric materials are commonly used as prosthetic patch materials. However, long-term clinical results have identified several issues that may be related to these materials used as patches including restenosis, pseudoaneurysm formation, infection, fibrosis, calcification and thrombosis (Li, et al., Ann Vasc Surg., 25(4): 561-568 (2011)).
Although open venous surgery is performed less frequently compared to open arterial surgery, patches are also used in venous surgery (Ohwada, et al., Hepatogastroenterology, 46, 855-858 (1999)), as venous procedures are frequently complicated by aggressive neointimal hyperplasia and restenosis, possibly due to the lower shear stress in the venous system. Gordon & Levi, Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology, 17, 206-211 (2008); Jia, et al., Nephrology, 20, 335-342, (2015); Chiu & Chien, Physiol Rev., 91, 327-387 (2011); Jiang, et al., FEBS Lett., 583, 3536-3540 (2009); and Dardik, et al., J Vasc Surg, 41, 869-880 (2005)).
Restenosis remains a common complication after angioplasty, endovascular angioplasty, and open patch angioplasty. A main cause of restenosis is neointimal hyperplasia, i.e. over-proliferation and migration of vascular muscle cells in the tunica intima, in the area at or near the patch, resulting in the thickening of blood vessel walls and luminal narrowing in vessels. In addition, patients with severe vascular disease may develop spontaneous venous neointimal hyperplasia (Korenblit, J. et al. Am Surg 80, E152-154 (2014)), placing them at additional risk after conventional venous interventions. The high rates of neointimal hyperplasia and restenosis after venous interventions shows the persistent clinical need for improved techniques or devices to treat patients with venous stenosis. The migration of smooth muscle cells from one tissue compartment to another followed by proliferation in the intima is regulated by factors released from thrombus (e.g. thrombin, PDGF), inflammatory cells (e.g. TNF, IL1b), or the vascular wall cells (bFGF, TGFβ, etc.). These factors as well as related signaling pathways, represent targets for pharmacological blockade and the prevention of intimal hyperplasia. For example, rapamycin (e.g. SIROLIMUS®) and taxol (e.g. PACLITAXEL®) and related adjuvant therapy are popular candidates for suppressing neointimal hyperplasia. However, oral administration of rapamycin induces systemic toxicity, leading to severe adverse effects including fever, anemia, and capillary leak syndrome (Kaplan et al, Arch Dermatol, 135(5):553-557 (1999)). Slow-release formulations of rapamycin reduce systemic toxicity and inhibit restenosis to some extent. Rapamycin-loaded nanoparticles reduced neointimal hyperplasia in animal models for both artery and vein injuries compared to no-drug controls (Reddy, et al., Circ Cardiovasc Intery, 1(3):209-216 (2008); Liu et al., Int J Nanomedicine, 5:853-860 (2010); and Zou, et al., Annals of vascular surgery 25, 538-546 (2011)). However, rapamycin-loaded nanoparticles are inconsistent in inhibiting restenosis. For example, intramural administration of slow released rapamycin from non-targeted nanoparticles in a rabbit femoral artery injury model does not differ from administration of saline, neither improving either neointimal hyperplasia, nor vascular stenosis. Integrin αvβ3-targeted nanoparticles delivering rapamycin did induce some improvement (Cyrus et al, Arterioscler Thromb Vasc Biol, 28:820-826 (2008)).
Another complication of vascular anastomotic techniques is the potential for development of anastomotic aneurysm. Although the incidence of anastomotic aneurysms is generally low, the prevalence of these aneurysms has increased as a result of the increase of vascular surgeries. The incidence of anastomotic aneurysms after carotid endarterectomy is about 0.3%, and accounts for 13%-57% of extracranial carotid aneurysms, including both true and pseudoaneurysms (Zhou, et al., J Vasc Surg. 43:493-496 (2006)).
Current formulations to deliver pharmaceuticals from prosthetic patches for the inhibition of restenosis have several disadvantages. Although pericardial patch angioplasty reduced the rate of restenosis in treated carotid arteries compared to primary closure and remained free from infection (Biasi, et al., J Vasc Surg, 36(2):271-277 (2002); Papakostas, et al., Ann Vasc Surg, 28(5):1213-1218 (2014)), the inhibition of restenosis in the venous models of patch angioplasty and the prevention of other complications associated with prosthetic patches in general require a drug delivery platform based on the patches. Several factors in current formulations hinder the successful delivery of pharmaceuticals from prosthetic patches. First, patches are stored “wet” and applied in a wet environment, resulting in easy detachment of unbound pharmaceuticals prior to, during and post application. Second, the dosage, kinetics and distribution of released pharmaceuticals need to be precisely controlled. There remains a need for improved prosthetic patch compositions that support localized, sustained delivery of active agents, while avoiding systemic or toxic side effects and minimizing undesired leaching.
Therefore, it is an object of the present invention to provide a composite prosthetic device that delivers active agents locally with a sustained release profile.
It is a further object of the present invention to provide methods of making the composite prosthetic device delivery system.
It is a further object of the invention to provide compositions, methods, and devices to promote healing and inhibit or prevent proliferative diseases and disorders in a subject.